Liquid preparation comprising pimobendan

ABSTRACT

The invention relates to novel liquid preparation comprising a substituted benzimidazol, preferably pimobendan as pharmaceutically active compound. In particular, the present invention relates to liquid preparation comprising an etherified cyclodextrin derivative, preferably in a concentration of about 20 to 70% (w/v) and said substituted benzimidazol, preferably in a concentration of about 0.005 to 0.15% (w/w).

RELATED APPLICATIONS

This application claims priority to European Application No. EP06123567.7, filed Nov. 7, 2006, the teachings and content of which arehereby incorporated by reference herein.

FIELD OF INVENTION

The invention relates to the field of medicine. In particular theinvention relates to novel liquid preparation comprising a substitutedbenzimidazol, preferably pimobendan as pharmaceutically active compound.

BACKGROUND OF THE INVENTION

Pimobendan is a well-known compound for the treatment of congestiveheart failure (CHF) originating for example from dilated cardiomyopathy(DCM) or decompensated endocardiosis (DCE) in animals, especially dogs(WO 2005/092343). Pimobendan is also approved as a drug product forcardiovascular treatment of humans.

Pimobendan(4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone)is disclosed in EP B-008 391, herein incorporated by reference in itsentirety, and having the formula:

As already was described in EP A-439 030 and WO 2005/08467, pimobendandrug substance is insoluble in water, 1g substance is soluble in morethan 10000 ml. At pH 7 the solubility of pimobendan is about 0.1 mg per100 ml.

The substance is administered by the oral route twice daily. Yet noliquid preparation comprising pimobendan is available. In order toachieve an immediate onset of action for all the innovative indicationsmentioned above, an injectable solution for parenteral administration bythe i.v. and/or s.c. route is obligatory. An aqueous formulation isrequired to administer a drug product by the i v./s.c. route to eitherhumans or animals, formulations with a non-aqueous solvent are neitheracceptable nor state of the art due to the risk of severe toleranceproblems.

Solubility in aqueous solutions is depending on the pH. The solubilityof pimobendan is significantly higher at pH 1 to 3, however, thechemical stability in solution is reduced so that a stable solution witha reasonable shelf-life cannot be achieved. In addition, the localtolerance of such a formulation is very poor. This is due to the factthat the target dose would require a drug concentration in solutionwhich can only be achieved by a pH of about pH3 and lower. The requiredconcentration in solution exceeds the solubility of pimobendan in waterby a factor of about 250, a factor of 1 to 1000 might be the maximumrequired increase.

Certain etherified beta-cyclodextrin derivatives are known to improvesolubility of sparingly soluble drugs (WO85/02767). However, inWO85/02767 only the use of etherified beta-cyclodextrin derivatives upto a concentration of 10% is described. A molar ratio of drug toetherified beta-cyclodextrin derivative of 136 to 431 was thought. Thesolubility of flubendazol within the above given ratio was onlyincreased by a factor 30. However, those formulations are not suitablefor the preparation of liquid preparations comprising pimobendan, or anyother substituted benzimidazol in therapeutically effective amounts ofup to 5 mg/ml preferably of 0.5 to 3 mg/ml, even more preferably of 0.5to 1.5 mg/ml. As mentioned above, at least pimobendan formulationcomprising up to 1.5 mg/ml needs an increase in solubility at pH 7 by afactor of about 1000 to 1500.

The objective underlying the present invention was to provide liquidpreparations comprising a substituted benzimidazol, preferablypimobendan as pharmaceutically active compound.

The objective underlying the present invention was to provide apharmaceutically acceptable solution comprising a substitutedbenzimidazol, preferably pimobendan as pharmaceutically active compound.

Another objective underlying the present invention was to provideinjectable solutions comprising a substituted benzimidazol, preferablypimobendan as pharmaceutically active compound.

DESCRIPTION OF THE INVENTION Description of the Figures

FIGS. 1 and 2 show the saturated solubility of pimobendan, a substitutedbenzimidazol in an aqueous solution comprising various concentrations ofthe etherified cyclodextrin derivative hydroxypropyl-beta-cyclodextrin(HPβCD) at pH 3, 5, and 7.

FIG. 3 shows the saturated solubility of pimobendan, a substitutedbenzimidazol in an aqueous solution comprising various 20 to 25% (w/v)of the etherified cyclodextrin-derivativehydroxypropyl-beta-cyclodextrin (HPβCD) dissolved in 10 mM phosphatebuffer at pH 7.

FIG. 4 shows the saturated solubility of pimobendan, a substitutedbenzimidazol in an aqueous solution comprising 24% (w/v) of theetherified cyclodextrin-derivative hydroxypropyl-beta-cyclodextrin(HPβCD) dissolved in 10 mM phosphate buffer and sodium chloride at pH 7.

FIG. 5 shows the effect of autoclaving on the soluble formulation ofpimobendan, a substituted benzimidazol.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention it shall be noted thatas used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “a preparation” includes aplurality of such preparations, reference to the “carrier” is areference to one or more carriers and equivalents thereof known to thoseskilled in the art, and so forth. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All given ranges and values may vary by 1 to 5%unless indicated otherwise or known otherwise by the person skilled inthe art, therefore, the term “about” was omitted from the description.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, the preferred methods, devices, and materials are nowdescribed. All publications mentioned herein are incorporated herein byreference for the purpose of describing and disclosing the substances,excipients, carriers, and methodologies as reported in the publicationswhich might be used in connection with the invention. Nothing herein isto be construed as an admission that the invention is not entitled toantedate such disclosure by virtue of prior invention.

The solution to the above technical problem is achieved by thedescription and the embodiments characterized in the claims.

The present invention is based on the unexpected observation that anon-linear relationship exists between the rise in concentration ofhydroxypropyl-beta-cyclodextrin (HPβCD), an etherified cyclodextrinderivative, and the increase in solubility of pimobendan a structurallymember of a substituted benzimidazol at a pH of about 5 or 7. Solutionscontaining a target concentration for pimobendan of about 0.5 to 1.5mg/ml could be obtained by the use of HPβCD concentration of more than15%, preferably of about 20% (w/v) to up to 70% (w/v) of the finalformulation. FIG. 1 teaches, that based on such a non-linearrelationship, a HPβCD concentration of more than 20 (w/v) caused in asignificant increased solubility of pimobendan, which is used in anexemplarily manner for a substituted benzimidazol. In general, by“(w/v)” as used herein is meant weight of substance per volume of thefinal preparation/formulation.

In addition, it was an unexpected observation that the solubilityenhancement achieved by HPβCD did not decrease at an increasing pH.Solubility of pimobendan at low pH values was in principle higher thanat higher pH values. This effect was already known from WO 2005/08467.This also was found for solutions comprising the etherified cyclodextrinderivative HPβCD (See FIG. 1). However, this effect surprisingly isreversed at pH 7.0. The solubility of pimobendan at pH 5 in the presenceof HPβCD was significantly reduced as compared to pH 3. Contrary, at pH7 the solubility of pimobendan in the presence of HPβCD is significantlyhigher than that pH 5. The relationship between increasing HPβCDconcentrations (by mass) and increase in saturated solubility ofpimobendan was linear at pH 3, but non-linear at pH 7 (see FIG. 1). Thehigher the concentration of HPβCD the higher the solubility ofpimobendan. This non-linear effects allows an increase of solubility ofmore than factor 1000, which is needed for the preparation of liquidpreparation of pimobendan, or any other substituted benzimidazolcomprising therapeutically effective amounts of those activeingredients.

Thus according to one aspect, the present invention relates to a liquidpreparation comprising an etherified cyclodextrin derivative and asubstituted benzimidazol, wherein the etherified cyclodextrin derivativeis selected from the group consisting of: alpha-, beta, andgamma-cyclodextrin ether.

The term “liquid preparation” as used herein, simply means that themajority of the preparation is present in liquid form. The term “liquidpreparation” as used herein, includes any form of an aqueous solution aswell as any kind of suspension. If the liquid preparation is obtained inthe form of a suspension, it is a dispersed system. By a “dispersedsystem” is meant, in general terms, a systems consisting of two or morephases in which one type of form (dispersed phase) is finely divided inthe other type of form (dispersion agent). By a “suspension” is meant,according to the invention, a mixture of solid particles in a liquid.Preferably, the liquid preparation according to the invention is anaqueous solution, more preferably a non-alcoholic aqueous solution. Evenmore preferably, those liquid preparations are aqueous solutions thatare suitable as injectable solutions for i.v. and/or s.c. application inanimals. The term “aqueous solution” as used herein, simply means thatthe majority of the preparation is present in a dissolved form. The termnon-alcoholic aqueous solutions as used herein means that preparation ispresent in a dissolved form but do not include alcoholic or otherorganic solvents.

Thus according to a further aspect, the present invention relates anaqueous solution comprising an etherified cyclodextrin derivative and asubstituted benzimidazol, wherein the etherified cyclodextrin derivativeis selected from the group consisting of: alpha-, beta, andgamma-cyclodextrin ether. Preferably, those aqueous solutions areinjectable solutions for i.v. and/or s.c. application in animals, or canbe can be used for the preparation of injectable solutions for i.v.and/or sec, application in animals.

The term etherified cyclodextrin derivatives as used herein includes butis not limited to alpha-, beta- or gamma-cyclodextrins. Preferably theetherified cyclodextrin derivatives as used herein means etherifiedbeta-cyclodextrins, more preferably of the formula:(beta-CD)-OR  (formula I),in which the residues R are hydroxyalkyl groups and part of the residuesR may optionally be alkyl groups. A partially etherifiedbeta-cyclodextrin of formula I is preferably used in which the residuesR are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups, Optionallypart of the residues R may for instance be methyl or ethyl groups; theuse of partially—methylated beta-cyclodextrin ethers with 7 to 14 methylgroups in the beta-cyclodextrin molecule as they are known from GermanOffenlegungsschrift 31 18 218 do not come under the present invention.Partial ethers of beta-cyclodextrin comprising only alkyl groups(methyl, ethyl) may be suitable in accordance with the invention if theyhave a low degree of substitution (as defined below) of 0.05 to 0.2.

Even more preferably, the etherified cyclodextrin derivative as usedherein is hydroxyethyl-beta-cyclodextrin,hydroxypropyl-beta-cyclodextrin, dihydroxypropyl-beta-cyclodextrin. Mostpreferably, the etherified cyclodextrin derivative as used herein ishydroxypropyl-beta-cyclodextrin (HPβCD), for example as described in theEuropean Pharmacopoeia (5^(th) Edition 2005, European Directorate forthe Quality of Medicines (EDQM), European Pharmacopoeia, 226 avenue deColmar, F-67029 Strasbourg, France, http:/www.pheur.org).Hydroxypropyl-beta-cyclodextrin (HPβCD) of pharmaceutical grade ismarketed for example under the Trademark Kleptose® HP and can be orderedfrom Roquette, France.

Beta-cyclodextrin is a compound with ring structure consisting of 7anhydro glucose units; it is also referred to as cycloheptaamylose. Eachof the 7 glucose rings contains in 2-,3-, and 6-position three hydroxygroups which may be etherified. In the partially etherifiedβ-cyclodextrin derivatives used according to the invention only part ofthese hydroxy groups is etherified with hydroxyalkyl groups andoptionally further with alkyl groups. When etherifying with hydroxyalkyl groups which can be carried out by reaction with the correspondingalkylene oxides, the degree of substitution is stated as molarsubstitution (MS), viz. in mole alkylene oxide per anhydroglucose unit,compare U.S. Pat. No. 3,459,731 column 4. In the hydroxyalkyl ethers ofbeta-cyclodextrin used in accordance with the invention the molarsubstitution is between 0.05 and 10, preferably between 0.2 and 2.Particularly preferred is a molar substitution of about 0.40 to about1.50. The etherification with alkyl groups may be stated directly asdegree of-substitution (DS) per glucose unit which as stated above—is 3for complete substitution. Partially etherified beta-cyclodextrins areused within the invention which comprise besides hydroxyalkyl groupsalso alkyl groups, especially a methyl or ethyl groups, up to a degreeof substitution of 0.05 to 2.0, preferably 0.2 to 1.5. Most preferablythe degree of substitution with alkylgroups is between about 0.5 andabout 1.2.

Thus, according to a further aspect, the present invention relates toliquid preparations as described above, comprising an etherifiedcyclodextrin derivative and a substituted benzimidazol, wherein theetherified cyclodextrin derivative is etherified beta-cyclodextrin.Preferably, that etherified beta-cyclodextrin ishydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, ordihydroxypropyl-beta-cyclodextrin. Even more preferably, that etherifiedbeta-cyclodextrin is hydroxypropyl-beta-cyclodextrin (HPβCD), forexample as described in the European Pharmacopoeia (5^(th) Edition 2005,European Directorate for the Quality of Medicines (EDQM), EuropeanPharmacopoeia, 226 avenue de Colmar, F-67029 Strasbourg, France,http:/www.pheurorg). Most preferably, that etherified beta-cyclodextrinis Kleptose® HP (Roquette, France).

The term “substituted benzamidazol” as used herein means, but is notlimited to thiabendazol, fuberdazol, oxibendazol, parbendazol,cambendazol, mebendazol, fenbendazol, flubendazol, albendazol,oxfendazol, nocodazol, astemisol and pimobendan, pharmaceuticalacceptable salts, derivatives, metabolites or pro-drugs thereof.Preferably, the term substituted benzimidazol as used herein meanspimobendan, or any pharmaceutical acceptable salts, derivatives,metabolites or pro-drugs thereof. Pimobendan as such is described supra.

Thus, according to a further aspect, the present invention relates toliquid preparations as described above, comprising an etherifiedcyclodextrin derivative and a substituted benzimidazol, wherein:

-   a) the etherified cyclodextrin derivative is etherified    beta-cyclodextrin, preferably, hydroxyethyl-beta-cyclodextrin,    hydroxypropyl-beta-cyclodextrin, or    dihydroxypropyl-beta-cyclodextrin, even more preferably    hydroxypropyl-beta-cyclodextrin (HPβCD), and most preferably,    Kleptose® HP (Roquette. France); and-   b) the substituted benzamidazol is thiabendazol, fuberidazol,    oxibendazol, parbendazol, cambendazol, mebendazol, fenbendazol,    flubendazol, albendazol, oxtendazol, nocodazol, astemisol or    pimobendan, pharmaceutical acceptable salts, derivatives,    metabolites or pro-drugs thereof, preferably pimobendan as described    supra or any pharmaceutical acceptable salt, derivative, metabolite    or pro-drug thereof.

The amount of etherified cyclodextrin that is needed for the liquidpreparation depends on the pH of the final liquid preparation, thesubstituted benzimidazol and the portion that is used. However, it wassurprisingly found, that the use of about 15-70% (w/v) of etherifiedcyclodextrin derivative, preferably HPβCD in the final preparation isappropriate to dissolve an therapeutically effective amount of any ofthe substituted benzimidazol described above. In particular, it isshown, that the use of about 15-70% (w/v) of etherified cyclodextrinderivatives as described above, preferably of HPβCD in the finalpreparation is appropriate to dissolve an therapeutically effectiveamount pimobendan. Thus, according to a further aspect, any of the finalliquid preparation as described herein, comprises about 15 to 70% (w/v)etherified cyclodextrin derivative, preferably HPβCD. Preferably theportion of etherified cyclodextrin derivative, preferably of HPβCD; ofthe final liquid preparation is 20-50% (w/v), even preferably 20-40%,even more preferably 20-30% (w/v), even more preferably 22-28%, evenmore preferably 23-27% (w/v), even more preferably 24-26% (w/v), forexample the portion of the final preparation is 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70% (w/v) or any fraction thereof.

The portion of the substituted benzimidazol of the liquid preparation asdescribed herein is as a rule between 0.005 and 0.15% (w/v), preferablybetween 0.01 and 0.15% (w/w), further preferred between 0.05 and 0.15%(w/w), and even further preferred between 0.075 and 0.10% (w/w).Consequently, the portion is, for example, 0.001, 0.002, 0.003, . . .0.008, 0.009, etc., 0.01, 0.02, 0.03, 0.04, 0.05, . . . 0.08 0.09 etc.;0.10, 0.11, 0.12 . . . 0.14, 0.15% (w/v). Preferably, the substitutedbenzimidazol is anyone of those described herein, preferably pimobendan.

Thus according to further aspect, the present invention relates to aliquid preparation comprising an etherified cyclodextrin derivative, anda substituted benzimidazol as described above, preferably HPβCD andpimobendan, wherein that liquid preparation comprises.

-   a) about 15 to 70% (w/v), preferably 20-50% (w/v), even preferably    20-40%, even more preferably 20-30% (w/v), even more preferably    22-28%, even more preferably 23-27% (w/v), most preferably 24-26%    (w/v) of such etherified cyclodextrin derivative, preferably of    HPβCD; and-   b) between 0.005 and 0.15% (w/v), preferably between 0.01 and 0.15    5% (w/w), further preferred between 0.05 and 0.15% (w/w), and even    further preferred between 0.075 and 0.1% (w/w) of a substituted    benzimidazol as described herein, preferably of pimobendan.

The general therapeutic effective target dose, in particular for thetreatment of acute CHF, but also for any other therapeutic use asdescribed herein is about 0.05 to 0.5 mg pimobendan per kg body weightof the animal, preferably about 01 to 0.3 mg pimobendan per kg bodyweight of the animal, even more preferably about 0.15 mg pimobendan perkg body weight of the animal. The target concentration of pimobendan inthe drug product should be set to 0.75 mg/ml allowing the administrationof safe and even injection volumes, E.g. a dog with a weight of 10 kgwould receive exactly a dose of 2 ml containing 1.5 mg of pimobendan.Thus according to a further aspect, the present invention relates to aliquid preparation, preferably an aqueous solutions for injection,comprising an etherified cyclodextrin derivative as described above,preferably HPβCD and 0.75 mg/ml (0.075% (w/v)) pimobendan. Morepreferably, the portion of etherified cyclodextrin derivative in thatliquid preparation comprises about 15 to 70% (w/v), preferably 20 50%(w/v), even preferably 20-40% (w/v), even more preferably 20-30% (w/v),even more preferably 22 28% (w/v), even more preferably 23-27% (w/v),most preferably 24-26% (w/v) of such etherified cyclodextrin derivative.Most preferred is a liquid preparation, preferably an aqueous solutionsfor injection, that comprises 0.75 mg/ml (0.075% (w/v)) pimobendan andabout 15 to 70% (w/v), preferably 20-50% (w/v), even preferably 20-40%(w/v), even more preferably 20-30% (w/v), even more preferably 22-28%(w/v), even more preferably 23-27% (w/v), most preferably 24-26% (w/v)HPβCD of the final formulation.

The liquid preparations are tolerable to the addition of buffers,antioxidants such as sodium edetate, isotonic agents such as sodiumchloride, and are suitable as single-use injectable solutions for i.v.and/or s.c. application in animals, especially dogs. Preservatives canbe added, too. Thus, according to a further aspect, the presentinvention relates to any of the above mentioned liquid preparations,preferably to aqueous solutions for injection, that comprise anetherified cyclodextrin derivative as described herein, preferablyHPβCD, and a substituted benzimidazol as described herein, preferablypimobendan, wherein such preparation further comprises pharmaceuticalacceptable excipients, and/or salts.

Purely by way of example, the excipients in a standard liquidpreparation, in particular in a solution for injection according to thepresent invention might be meglumin, macrogol, poloxamer 188, parabensand glycin. The formulations according to the invention may containcomplexing agents as other ingredients. By complexing agents are meantwithin the scope of the present invention molecules which are capable ofentering into complex bonds. Preferably, these compounds should have theeffect of complexing cations, most preferably metal cations. Theformulations according to the invention preferably contain edetic acid(EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodiumEDTA dihydrate (sodium edetate), as complexing agent. Preferably, sodiumedetate is used, optionally in the form of its hydrates, more preferablyin the form of its dihydrate. If complexing agents are used within theformulations according to the invention, their content is preferably inthe range from 1 to 20 mg per 10 ml, more preferably in the range from 2to 10 mg per 10 ml of the formulation according to the invention.Preferably, the formulations according to the invention contain acomplexing agent in an amount of about 5 mg per 10 ml of the formulationaccording to the invention. Of course, other excipients known to theskilled man may also be used.

Thus, according to a further aspect, the present invention relates toany of the above mentioned liquid preparations, preferably to aqueoussolutions for injection, that comprise an etherified cyclodextrinderivative as described herein, preferably HPβCD, and a substitutedbenzimidazol as described herein, preferably pimobendan, wherein suchpreparation further contains one or more suitable preservative(s),preferably selected from the group consisting of meglumin, macrogol,parabens and EDTA.

In the case of the salts these are, for example, inorganic salts such aschloride, sulfate, phosphate, diphosphate, bromide and/or nitrate salts.Furthermore, the powders according to the invention may also containorganic salts such as malate, maleate, fumarate, tartrate, succinate,ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate,ascorbate, para-toluenesulfonate, palmoate, salicylate, stearate,estolate, gluceptate or lactobionate salts, for example. At the sametime, corresponding salts may contain pharmaceutically acceptablecations such as sodium, potassium, calcium, aluminum, ammonium, forexample.

However, it is shown by the present invention, that the salt mightreduce the solubility of pimobendan in the presence of fix amount ofHPβCD. There are two ways to overcome this problem. The first option isto further increase the concentration of HPβCD. The other way is to keeprestrict the amount of salts. It was shown, that after addition ofphosphates resulting in an osmolality of about 300 mOsm/Kg thesolubility of pimobendan in an exemplarily manner was not affected.Thus, according to a further aspect, the present invention relates toany of the above mentioned liquid preparations, preferably to aqueoussolutions for injection, that comprise an etherified cyclodextrinderivative as described herein, preferably HPβCD, and a substitutedbenzimidazol as described herein, preferably pimobendan, wherein suchliquid preparation contains an osmolality of about 250 to 350 mOsm/Kg,preferably of about 270 to 320 mOsm/Kg, even more preferably of about280 to 300 mOsm/Kg. A person skilled in the art is able to adjust theosmolality of any of such liquid preparations to the above mentionedranges by means well known in the art. For example, a liquid preparationthat comprises about 24% (w/v) HPβCD and 0.75 mg/ml pimobendan maycontain 10 mM of an alkali phosphate, preferably of sodium phosphate toadjust the osmolality of the final liquid preparation to about 290 to300 mOsm/kg.

The pH of the liquid preparation according to the invention ispreferably between 5.5 and 8.5. In particular, in case of an injectablesolution, the pH is preferably between 6.5 and 7.5. Preferred buffersystems that can be used to adjust the pH to 6.5 to 7.5 are, forexample, phosphate, acetate and citrate buffer systems. Preparations ofany of those buffer systems are described for example in the EuropeanPharmacopoeia (5^(th) Edition 2005, European Directorate for the Qualityof Medicines (EDQM), European Pharmacopoeia, 226 avenue de ColmarF-67029 Strasbourg, France, http://www.pheur.org). Thus, according to afurther aspect, the present invention relates to any of the abovementioned liquid preparations, preferably to aqueous solutions forinjection, that comprise an etherified cyclodextrin derivative asdescribed herein, preferably HPβCD, and a substituted benzimidazol asdescribed herein, preferably pimobendan, wherein such liquid preparationis adjusted to pH 5.5 to 8.5, preferably to pH 6.5 to 7.5 in case of aninjectable solution.

As described above, a preferred embodiment of the present inventionrelates to an injectable solution adjusted to pH 6 to 7.5, that comprisean etherified cyclodextrin derivative as described herein, preferablyHPβCD, and a substituted benzimidazol as described herein, preferablypimobendan. In such case, the preparation of an isotonic solution wouldfurther be preferred.

In order to achieve an immediate onset of action of the substitutedbenzimidazol, preferably of pimobendan for all suitable indications, aninjectable solution for parenteral administration by the i.v. and/ors.c. route is obligatory. An aqueous formulation is required toadminister a drug product by the i.v./s.c. route to either humans oranimals, formulations with a non-aqueous solvent are neither acceptablenor state of the art due to the risk of severe tolerance problems.

Thus according to a further aspect, the current invention relates to aninjectable solution, i.e. for parenteral administration by the i.v.and/or s.c. route, comprising any of the liquid preparation as describedabove. It might be useful to administer the drug continuously over adefined period of time and not in a one-shot application. In such case,administration of an aqueous solution comprising the substitutedbenzimidazol, preferably pimobendan by infusion is advantageous. Thusaccording to a further aspect, the current invention relates to aninjectable solution for infusion, comprising any of the liquidpreparation as described above.

A solution is absolutely necessary for i.v. administration, suspendedparticles bear a high risk of emboli and have to be excluded.Ready-to-use solutions are preferred compared to lyophilised productswhich have to be reconstituted by adding a diluent/solvent beforeadministration. The reconstitution of a drug product to be administeredwill add several minutes to the treatment which has to be avoided in alife-threatening situation as this. In addition local tolerance willdepend on the isotonicity and pH range of the formulation. A pH in theneutral range of about pH 7 is usually preferred, the higher the actualpH deviates from this target the more likely the risk of not acceptablelocal tolerance.

Thus, according to a further aspect, the invention relates to any of theliquid preparations described herein and comprising an etherifiedcyclodextrin derivative as described herein, preferably HPβCD and asubstituted benzimidazol as described herein, preferably pimobendanwherein the liquid solution is a Ready-to use solution. The Ready-to-usesolution is in general adjusted to a pH of about 6.5 to 7.5, preferablyof about 6.8 to 7.2, even more preferred of about 7.0. Moreover, thatReady-to-use solution is also adjusted to an osmolality of about 250 to350 mOsm/Kg, preferably of about 270 to 320 mOsm/Kg, even morepreferably of about 280 to 300 mOsm/Kg. It was surprisingly found, thatthe addition of some salts resulting in about 300 mOsm/Kg significantlyreduce the solubility of the substituted benzimidazol, in particular ofpimobendan. However, it is in the knowledge of a person skilled in theart to slightly increase the osmolality of that Read-to-use solution toabout 300 mOsm/Kg, e.g. to about 305 to 310 mOsm/Kg, that an appropriatesolubility of the substituted benzimidazol, in particular of pimobendanis ensured.

According to a further aspect, the present invention relates to a liquidpreparation as described supra, wherein the preparation comprises abouti) 20 to 30% (w/v) of a HPβCD; ii) 0.005 to 0.15% (w/w) pimobendan, apharmaceutical acceptable salt, derivative, metabolite or pro-drugthereof, and optional iii) 0.025 to 0.075% (w/w) of stabilizerpreferably EDTA; and wherein the pH of the liquid preparation isadjusted to about 6.5 to 7.5 and the osmolality is about 280 to 300mOsm/Kg.

According to a further aspect, the present invention also relates to amanufacturing process for the production of any of the liquidpreparation as described herein. In the knowledge of the specificformulation of any of the above described liquid formulation, thoseformulations can be prepared according to stand procedures known to aperson skilled in the art. That process comprises the steps:

-   a) Dissolving the etherified cyclodextrin derivative in a solvent;-   b) Adding the substituted benzimidazol to the solution obtained in    step (a); and-   c) Admixing the mixture obtained in step (b) to obtain the liquid    preparation in the form of an aqueous solution.

Preferably, that etherified cyclodextrin derivative is HPβCD. Moreover,the solvent preferably is water for injection.

According to more preferred embodiment that manufacturing processcomprises the steps:

-   a) Weight the etherified cyclodextrin, preferably HPβCD into the    manufacturing container;-   b) Add water to approximately 40 to 80% of the final volume;-   c) Mix until the etherified cyclodextrin dissolves using magnetic    stirred or paddle stirrer;-   d) Add any buffer component(s), transfer with water and mix until    dissolved;-   e) Check pH to ensure that it is close to the set-point. Adjust with    sodium hydroxide or hydrochloric acid if required;-   f) Add the substituted benzimidazol, preferably pimobendan, transfer    with water and mix until dissolved;-   g) Make to volume with water;

According to a even more preferred aspect, the manufacturing processcomprises the steps:

-   h) Filter the liquid preparation of step g) and dispense into vials;-   i) Autoclave the vials, preferably for 30 min at 121° C.

According to a further aspect, the present invention relates to the useof any of the liquid preparation as described herein as a medicament.Preferably that medicament is a veterinary medicament. Even morepreferred, that medicament is a solution for injection. That solutionfor injection is, according to a further aspect an infusion solution.

As described supra, there is an unmet need in the field of medicineregarding the treatment of acute congestive heart failure (acute CHF) inanimals and humans, and especially in dogs. Thus, the liquid preparationas provided herewith can be used in human and veterinary medicine,preferably in veterinary medicine. No product is licensed in veterinarymedicine for this indication so far. So the treatment of acute CHF in alife-threatening situation would be an important innovation allowing tosave the animal's life in an acute crisis situation. Due to an immediateonset of action, the rapid visual change of the animal's status wouldallow both the veterinarian and the animal owner to evaluate the successof the measures taken to overcome the situation. Additionally, this wayof treatment would be a therapy option in cases where oral treatment isnot possible. Peri-operative administration to maintain cardiovascularfunction and/or renal perfusion during anaesthesia as well as treatmentof shock and/or gastric dilation volvulus situations are other potentialindications for a pimobendan formulation with an immediate onset.

Thus, according to a further embodiment, the present invention alsorelates the use of any of the liquid preparation comprising pimobendandescribed herein for preparing a pharmaceutical composition for thetreatment or prevention of diseases in a subject in need of suchtreatment, selected from among the indications: congestive heart failure(CHF), acute CHF, decompensated endocardiosis (DCE), dilatedcardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM,maintenance of cardiovascular function and/or renal perfusion duringanaesthesia, shock, gastric dilation, volvulus, myocardial and renalischemia. As described supra, the general therapeutically effectiveamount of pimobendan is about 0.05 to 0.5 mg pimobendan per kg bodyweight of the animal and application, preferably about 0.1 to 0.3 mgpimobendan per kg body weight of the animal and application, even morepreferably about 0.15 mg pimobendan per kg body weight of the animal.Preferably, one dose is to be administered per day.

According to a further aspect, the present invention also relates tomethod of treatment and/or prevention of diseases, wherein cardiotonic,hypotensive, anti-inflammatory and anti-thrombotic substances have atherapeutic benefit comprising the step: administering to such subjectin need of such treatment a therapeutically effective amount of any ofthe liquid preparations as described herein. Preferably, the liquidpreparation is administered to a therapeutically effective amount ofabout 0.05 to 0.5 mg pimobendan per kg body weight of the animal andapplication, preferably about 0.1 to 0.3 mg pimobendan per kg bodyweight of the animal and application, even more preferably about 0.15 mgpimobendan per kg body weight of the animal. Preferably, one dose is tobe administered per day.

As mentioned above, pimobendan is a well established medicament in thetreatment of congestive heart failure (CHF), decompensated endocardiosis(DCE), dilated cardiomyopathy (DCM), asymptomatic (occult) CHF,asymptomatic DCM, among others. Thus according to a further aspect, thepresent invention directly relates to a method of treatment and/orprevention a subject suffering on or having a congestive heart failure(CHF), decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM),asymptomatic (occult) CHF, asymptomatic DCM, myocardial and renalischemia, shock, comprising the step: administering to said subject inneed thereof any of the liquid preparations described herein andcomprising a therapeutically effective amount of pimobendan. Inparticular, the therapeutically effective amount for the treatment ofCHF is about 0.05 to 0.5 mg pimobendan per kg body weight of the animaland application, preferably about 0.1 to 0.3 mg pimobendan per kg bodyweight of the animal and application, even more preferably about 0.15 mgpimobendan per kg body weight of the animal and application. Preferably,one dose is to be administered per day. Such a treatment is alsoadvantageous in the case of maintenance of cardiovascular functionand/or renal perfusion during anaesthesia, shock, gastric dilation orvolvulus, for examples caused by surgery, especially gastrointestinalsurgery as well as trauma.

The subject in need of any such treatment mentioned above is a mammal,preferably a human or an animal. The term animal as used herein includesbut is not limited to companion animals such as dogs, cats, guinea pigs,hamsters, horses, cattle, goats, sheeps or the like. Preferably, thesubject in need of such treatment is a dog, horse or cat, mostpreferably a dog. However, such animal in need of such treatment alsoincludes zoo animals such as monkies, elephants, giraffes and otherungulates, bears, mice and other small mammals.

The present invention furthermore relates to a kit of parts, thatcomprises

-   a) a container with a liquid preparation, preferably an injectable    solution, according to the present invention as described herein,-   b) and a package leaflet including the information that the liquid    preparation, preferably the injectable solution, according to the    present invention is to be used, preferably via injection (s.c. or    i.v.), for the prevention and/or treatment of congestive heart    failure in a subject in need of such prevention or treatment,    preferably in a mammal as defined above.

In case of the treatment of an animal, that package leaflet preferablyincludes the information that the pimobendan is to be used at a dose asdescribed supra, preferably of about 0.15 mg per kg body weight andapplication. Preferably, one dose is to be administered per day. Morepreferably, the package-leaflet includes the specific indication asdescribed above.

According to a further aspect, the container comprises 2 ml, 5 ml, 10ml, 50 ml, or 250 ml of the liquid preparation. Preferably the containercomprises 3.75, 7.5 or 37.5 mg pimobendan.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example: 1 Solubility of Pimobendan in the Presence ofhydroxypropyl-beta-cyclodextrin (HPβCD) at Different pH Values

The solubility of pimobendan, a substituted benzimidazol, was tested atvarious concentrations of hydroxypropyl-beta-cyclodextrin (HPβCD) and atpH 3, 5 and 7. Kleptose® HP (Roquette, France) was used as HPβCD ofpharmaceutical grade.

Saturated solubility of pimobendan was investigated at 10 to 40% (w/v)of HPβCD at pH 3, 5, and 7. The solutions were buffered with a sodiumphosphate solution. The sample solutions were prepared using thefollowing method:

-   a) Approximately 3 ml of the solution under test was placed in a 7    ml glass vial with a magnetic stirring bar.-   b) The pH was adjusted with hydrochloric acid-   c) An excess of pimobendan was added. The sample was placed in an    ultrasonic bath and sonicated for 5 min. to ensure an excess of    pimobendan was present and more added if required;-   d) The samples were placed in a water bath at 2500 and stirred for    at least 16 hours,-   e) The samples were filtered using 0.2 μm PVDF syringe filter.-   f) The samples were assayed by HPLC.

The results are shown in FIGS. 1 and 2. It was surprisingly found thatdue to a non-linear relationship between the rise in concentration ofHPβCD and the increase in solubility of pimobendan both at a pH of about5 or 7, solutions containing the target concentration for pimobendancould be obtained by the use of (HPβCD) concentration of more than 15%.(see FIG. 1). In addition, it was an unexpected observation that thesolubility enhancement achieved by HPβCD did not increase withdecreasing pH, but that at pH 7 the solubility at a certain HPβCDconcentration was lower at pH 7 than at pH 3, but higher than at pH 5.The relationship between increase of HPβCD concentration (by mass) andincrease in saturated solubility of pimobendan was linear at pH 3, butnon-linear at pH 5 and pH 7 (see FIG. 2).

Example: 2 Formulation Development

1. Level of hydroxypropyl-beta-cyclodextrin (HPβCD)

Saturated solubility of pimobendan was investigated at 20 to 25% (w/v)of HPβCD in 10 mM phosphate buffer pH 7.0. The study was carried out onthree different batches of HPβCD and each solution tested in duplicate(see FIG. 3). The solutions were prepared using the following method;

-   a) Approximately 3 ml of the solution under test was placed in a 7    ml glass vial with a magnetic stirring bar,-   b) An excess of pimobendan was added. The sample was placed in an    ultrasonic bath and sonicated for 5 min. to ensure an excess of    pimobendan was present and more added if required.-   c) The samples were placed in a water bath at 25° C. and stirred for    at least 16 hours.-   d) The samples were filtered using 0.2 μm PVDF syringe filter.-   e) The samples were assayed by HPLC.

A level of 22 to 24% (w/v) HPβCD was chosen for the formulationscomprising 0.5, 0.75 and 1.0 mg/ml pimobendan.

2. Osmolality:

An isotonic solution was required for the formulation. The formulationwith 24% (w/v) HPβCD and 10 mM phosphate buffer had an osmolality of 287mOsm/Kg. Sodium chloride was added to increase the osmolality to 303mOsm/Kg. Saturated solubility of pimobendan 0.75 mg/ml at 24% (w/v)HPβCD were investigated and results were compared with thoseformulations that were not supplemented with sodium chloride. Resultsare shown in FIG. 4. The amount of soluble pimobendan dramaticallydecreases from about 1.23 mg/ml to about 0.71 mg/ml.

3. Physical Stability:

A sample of the final formulation comprising 24% (w/v) HPβCD, 0.75 mg/mlpimobendan, 10 mM phosphate buffer, pH 7.0 was filtered through a 0.2 μmsyringe PVDF filter into two screw cap class vials. One vial was storedat room temperature and the other at 5° C. Samples were assessedinitially, after one and after two weeks for changes in appearance andsign of precipitation. No changes in appearance and no sign ofprecipitation were observed.

3. Filter Studies and Autoclaving Studies:

A) A sample of the final formulation comprising 24% (w/v) HPβCD, 0.75mg/ml pimobendan, 10 mM phosphate buffer, pH 7.0 was filtered throughthree different filters (Fluorodyne® 0.2 μm (Pall); Durapore®, 0.22 μm(Millipore) and Supor® 0.2 μm (Pall)). For each experiment, 30 ml of thetest solution was placed in a 50 ml syringe and then forced through anin-line holder housing a 47 mm membrane of each type. Filtrate sampleswere collected at sampling points 1, 2, 3, 4, 5, 10, 15 and 25 ml andanalyzed to its pimobendan content. No change in the pimobendan contentwas measured for each filter system.B) A sample of the final formulation comprising 24% (w/v) HPβCD, 0.75mg/ml pimobendan, 10 mM phosphate buffer, pH 7.0 was filtered through a0.2 μm syringe PVDF filter and the filtrate was autoclaved at 121° C.for 30 min. The results are shown in FIG. 5. Only a small amount ofdegradation was observed when the formulation was autoclaved. The levelwas very low and indicates that the formulation can be autoclaved.

Example: 3 Manufacturing Process

The manufacturing process for the preparation of final formulationcomprising HPβCD and pimobendan, is:

-   a) Weight the HPβCD into the manufacturing container;-   b) Add water to approximately 60% of the final volume;-   c) Mix until HPβCD dissolves using magnetic stirred or paddle    stirrer;-   d) Add the buffer components transfer with water and mix until    dissolved;-   e) Check pH to ensure that it is close to pH 7.0. Adjust with sodium    hydroxide or hydrochloric acid if required;-   f) Add pimobendan, transfer with water and mix until dissolved;-   g) Make to volume with water;-   h) Filter the solution and dispense into vials;-   i) Autoclave the vials for 30 min at 121° C.

Example: 4 Liquid Preparations

A) mg/10 ml Material Formulation # 1 Formulation # 2 Pimobendan 10 7.5Kleptose HP (HPβCD) 3000.0 3000.0 Citric acid 200.0 200.0 monohydrateNaOH 0.1N q.s. ad pH 6.0 q.s. ad pH 6.0 Disodium edetate 5.0 5.0 Waterfor injection q.s. to 10 ml q.s. to 10 ml

B) mg/10 ml Material Formulation # 1 Formulation # 2 Pimobendan 10 7.5Kleptose HP (HPβCD) 2600.0 2400.0 Disodium hydrogen 0.1343 0.1343phosphate dodecahydrate Sodium dihydrogen 0.0975 0.0975 phosphatedihydrate Water for injection q.s. to 10 ml q.s. to 10 ml

c) mg/10 ml Material Formulation # 1 Formulation # 2 Pimobendan 10 7.5Kleptose HP (HPβCD) 2600.0 2400.0 Disodium hydrogen 0.1343 0.1343phosphate dodecahydrate Sodium dihydrogen 0.0975 0.0975 phosphatedihydrate Disodium edetate 5.0 5.0 Water for injection q.s. to 10 mlq.s. to 10 ml

D) mg/10 ml Material Formulation # 1 Formulation # 2 Pimobendan 10.0 7.5Kleptose HP (HPβCD) 3300.0 3000.0 Disodium hydrogen 17.6 17.6 phosphatedodecahydrate Sodium dihydrogen 8.0 8.0 phosphate dihydrate Methylparaben 20.0 10.0 Propyl paraben 5.0 5.0 Disodium edetate 5.0 5.0 Waterfor injection q.s. to 10 ml q.s. to 10 ml

E) mg/10 ml Material Formulation # 1 Formulation # 2 Pimobendan 10 7.5Kleptose HP (HPβCD) 2500.0 2300.0 Disodium hydrogen 17.6 17.6 phosphatedodecahydrate Sodium dihydrogen 8.0 8.0 phosphate dehydrate Disodiumedetate 5.0 5.0 Water for injection q.s. to 10 ml q.s. to 10 ml

The invention claimed is:
 1. A liquid preparation comprising: about 20to 30% (w/v) of an etherified cyclodextrin derivative selected from thegroup consisting of alpha-, beta- and gamma-cyclodextrin ethers; andabout 0.075 to 0.1% (w/v) of pimobendan or a pharmaceutically acceptablesalt thereof, wherein the molar ratio of pimobendan or thepharmaceutically acceptable salt thereof to the etherified cyclodextrinderivative is about 1:47 to about 1:96.
 2. The liquid preparationaccording to claim 1, wherein the etherified cyclodextrin derivative ishydroxypropyl-beta-cyclodextrin.
 3. The liquid preparation according toclaim I, wherein the preparation further comprises pharmaceuticalacceptable carriers, excipients, and/or salts.
 4. The liquid preparationaccording to claim 1, wherein the preparation is isotonic.
 5. The liquidpreparation according to claim 1, wherein the preparation has pH valueof about 6.5 to 7.5 and an osmolality of about 280 to 300 mOsm/Kg. 6.The liquid preparation according to claim 1, wherein the preparationcontains one or more suitable preservative/s.
 7. The liquid preparationaccording to claim 1, wherein the etherified cyclodextrin derivative ishydroxypropyl-beta-cyclodextrin; and wherein the pH of the liquid isadjusted to about 6.5 to 7.5 and the osmolality is about 280 to 300mOsm/Kg.
 8. The liquid preparation according to claim 7, wherein theliquid preparation further comprises 0.025 to 0.075% (w/v) of one ormore stabilizers.
 9. A process for producing a liquid preparationaccording to claim 1, comprising the steps: dissolving the etherifiedcyclodextrin derivative in a solvent, adding the pimobendan orpharmaceutically acceptable salt thereof to the solution obtained instep (a) and admixing the mixture obtained in step (b) to obtain theliquid preparation in the form of an aqueous solution.
 10. The processaccording to claim 9, wherein the solvent is water.
 11. A method oftreatment of a subject having a congestive heart failure comprising thestep: administering to said subject in need of such treatment a liquidpreparation according to claim
 1. 12. The method according to claim 11,wherein the subject is a non-human animal.
 13. The method according toclaim 11, wherein said administration is by injection or infusion.
 14. Amethod of treating a subject comprising: administering to a subject inneed of treatment a liquid preparation according to claim 1, wherein thesubject suffers from a condition selected from the group consisting ofcongestive heart failure (CHF), acute CHF, decompensated endocardiosis(DCE), dilated cardiomyopathy (DCM), asymptomatic (occult) CHF,asymptomatic DCM, maintenance of cardiovascular function and/or renalperfusion during anaesthesia, shock, gastric dilation, volvulus,myocardial and renal ischemia.
 15. The method according to claim 14,wherein the subject in need of such treatment is a horse, dog or cat.16. A kit of parts that comprises: liquid preparation according to claim1; and a package leaflet including the information that the liquidpreparation is to be used for the prevention of congestive heart failurein a subject in need of such treatment.
 17. The liquid preparationaccording to claim 1, wherein the etherified cyclodextrin derivative ispresent in an amount of about 20 to 50% (w/v).
 18. The method accordingto claim 14, wherein said administration is by injection or infusion.